Neutrophil (PMN) activation plays a central role in diverse host responses, such as host defense, inflammation and reperfusion injury (Weissmann, G., Smolen, J. E., and Korchak, H. M. (1980) Release of inflammatory mediators from stimulated neutrophils. N. Engl. J. Med. 303, 27-34). In response to inflammatory stimuli, PMN phospholipases are activated to remodel cell membranes and generate bioactive lipids that serve as intra- or extracellular mediators in the transduction of functional responses (Serhan, C. N., Haeggstrom, J. Z., and Leslie, C. C. (1996) Lipid mediator networks in cell signaling: update and impact of cytokines. FASEB J. 10, 1147-1158). Important components of microbicidal and acute inflammatory responses include reactive oxygen species and granule enzymes that are targeted to phagocytic vacuoles, but aberrant release of these potentially toxic agents can lead to amplification of inflammation as well as tissue injury and are implicated in a wide range of diseases (Weiss, S. J. (1989) Tissue destruction by neutrophils. N. Engl. J. Med. 320, 365-376). To prevent an over-exuberant inflammatory response and limit damage to the host, these PMN programs are tightly regulated. The host mediators serving as endogenous anti-inflammatory or protective signals are only recently being appreciated (Serhan, C. N. (1994) Lipoxin biosynthesis and its impact in inflammatory and vascular events. Biochim. Biophys. Acta 1212, 1-25).
The present invention pertains to methods for modulating a disease or condition associated with phospholipase D (PLD) activity. The methods include administration to a subject, an effective anti-PLD amount of a lipoxin analog having the formula described infra, such that the PLD initiated activity is modulated.
The present invention also pertains to methods for treating phosphlipase D (PLD) activity in a subject. The methods include administration of an effective anti-PLD amount of a lipoxin analog described infra, such that PLD initiated activity is treated.
The present invention further pertains to methods for modulating a disease or condition associated with phospholipase D (PLD) initiated generation of superoxide or degranulation activity in a subject. The methods include, administration of an effective anti-PLD amount of a lipoxin analog described infra, such that a disease or condition associated with initiated by PLD generation of superoxide or degranulation activity, is modulated.
The present invention further relates to methods for treating phospholipase D (PLD) initiated superoxide generation or degranulation activity in a subject. The methods include administration of an effective anti-PLD amount of a lipoxin analog described infra, such that PLD initiated superoxide generation or degranulation activity is treated.
In preferred embodiments, the methods of the invention are performed in vitro or in vivo.
In another aspect, the present invention is directed to a packaged pharmaceutical composition for treating the activity or conditions listed above in a subject. The packaged pharmaceutical composition includes a container holding a therapeutically effective amount of at least one lipoxin compound having one of the formulae described infra and instructions for using the lipoxin compound for treating the activity or condition in the subject.